Gene therapy is arguably the most important conceptual advance in the treatment of human disease in the modern era of medicine. The potential benefits and applications are almost unlimited and promising new strategies are emerging at a rapid pace. A great deal has been learned and the field as matured significantly through fundamental studies using animal model systems and through practical experience gained in clinical trials. While the Program Project has accomplished perhaps the first successful clinical application of gene therapy, there remain impediments to the general implementation of gene therapy. These relate primarily to the need to improve the technology of gene transfer and appropriate gene expression in the target tissue. The goal of this renewal application remains the further development of gene therapy as a practical tool of medicine through studies that encompass the improvement of gene transfer vectors and application to animal models of metabolic disease having a recognizable genetic component. In this revised application five projects and three cores are proposed which represent a natural extension of previous work done to fulfill the aims of the current grant and respond to criticisms of the initial competing renewal application. The projects include studies to further develop novel vector systems for gene transfer (e.g. herpesvirus vectors, helper-free adeno-associated virus vectors and chylomicrons), explore the potential for gene transfer to animal models of disease, devise methods for treatment of monogenetic metabolic diseases that affect peripheral nerves and liver and devise novel immunomodulatory methods for the treatment of arthritis and diabetes. The current research program has enjoyed the support of outstanding core programs in Cell and Tissue Imaging, Vector Development, and administration and their continuance is proposed. Although we are no longer requesting support for the Human Gene Therapy Applications Laboratory (HGTAL), it continues to be supported by other grants and contracts and is available should any of our projects advance to the level of phase I clinical trials. The renewal application reflects our commitment to translate gene therapy research on model systems to delivery of gene therapy to patients and remains a central program of the Pittsburgh Human Gene Therapy Center (PHGTC).